Rapid development of contrast agents in the recent years has generated a number of different formulations, which are useful in contrast-enhanced imaging of organs and tissue of human or animal body.
More recently, attention has been given to so-called “molecular imaging”, where suitable target specific components are used in the formulation of the contrast agents, for allowing selective contrast-enhanced imaging of organs or tissues. In addition, therapeutic use of contrast agent formulations, optionally in combination with molecular imaging, has also been described.
A class of contrast agents, particularly useful for ultrasound contrast imaging, includes suspensions of gas bubbles of nano- and/or micro-metric size dispersed in an aqueous medium. Of particular interest are those formulations where the gas bubbles are stabilized, for example by using emulsifiers, oils, thickeners or sugars, or by entrapping or encapsulating the gas or a precursor thereof in a variety of systems. These stabilized gas bubbles are generally referred to in the art with various terminologies, such as, for instance, “microvesicles”, “microspheres”, “microbubbles”, “microcapsules” or “microballoons”. In the present description and claims, the term “microvesicles” is used to identify any of the above described stabilized gas-bubbles.
The formulations of gas-filled microvesicles can be suitably modified, either for improving the diagnostic effect (e.g. through molecular imaging) and/or for therapeutic purposes, such as drug delivery and/or thrombolysis. For instance, microvesicles can be associated (e.g. by inclusion in their boundary envelope) with therapeutic agents and/or with specific components which are capable to link to a determined target within a patient's body (known as “targeting ligands”). Examples of targeting ligands include, for instance, peptides, proteins or antibodies, capable of binding to specific organ or tissue such as, for instance, angiogenic or thrombolitic tissue.
A possible way to associate a targeting ligand or a therapeutic compound to the structure of a microvesicle is to bind it to suitable molecules which can be employed for the formation of the microvesicles envelope. The targeting or therapeutic component can be directly linked to the envelope-forming molecule or through a suitable spacer, in general a polymeric spacer.
Association of targeting ligands or therapeutic agents to microvesicles through a spacer is disclosed, for instance, in WO 96/40285, WO 98/18501, WO 98/53857.
In view of the large variety of possible targeting ligands and therapeutic agents, having different physico-chemical properties, it would be desirable to develop additional spacer moieties to effectively bind said targeting ligands or therapeutic agent to a component associated with the envelope of gas-filled filled microvesicles.
The applicant has now found a new component which can be suitably employed as a spacer (“S”) for bridging a targeting ligand or a therapeutic agent and an envelope-forming molecule. Said component comprises at least two sulfone groups (—SO2—) and is suitably functionalized to bridge conventional moieties capable of being associated with an envelope of a gas-filled microvesicle (component “M”) with a targeting ligand or therapeutic agent (component “T”), in a compound of formula M-S-T.
As observed by the applicant, the high hydrophilicity of the at least two sulfone groups included into the spacer component “S” allows to use spacers of relatively short length, as compared to longer polymeric spacers, even in those cases where the component T has a relatively high hydrophobicity.